Implantable medical devices having thin polymeric coatings containing therapeutic compounds that are released from the coating to provide a local therapeutic effect in the vicinity of the coated device have been shown to be valuable for the treatment of various medical conditions, in particular those conditions involving diseases of the cardiovascular system. For example, delivery of a therapeutic agent from the device surface can prevent cellular responses initiated by the presence of the implantable device. The therapeutic agent that is released from the coating can prevent conditions that would otherwise shorten the functional life of the device following implantation. Therapeutic agents released from the coating may also be directed at treating a diseased area of the body.
For example, stents having a coating containing a therapeutic agent can provide localized release of a therapeutic substance at the site of administration. Local administration of therapeutic agents via polymeric coatings on stents has shown favorable results in reducing restenosis. Several classes of drug-polymer chemistries have been explored for use in stent coatings as found in current art, some of which have been approved and are currently being used in medical procedures. Many of these chemistries are useful for delivering hydrophobic therapeutic agents.
For example, coating compositions based on poly(alkyl(meth)acrylate) and poly(ethylene-co-vinyl acetate) mixtures suitable for preparing coatings for hydrophobic drug (such as rapamycin) release are described in U.S. Pat. No. 6,214,901. Release of hydrophobic bioactive agents in a controlled manner can be achieved using this type of polymeric coating system. For example, sustained and controlled release of the hydrophobic drug, wherein less than 50% of the total quantity of the hydrophilic drug released is released in the first 24 hours.
Another hydrophobic polymer system stated to be useful for drug delivery is described in U.S. Pat. No. 6,669,980, which teaches preparation of medical devices having coatings that include poly(styrene-isobutylene-styrene).
Yet other hydrophobic polymer systems useful for drug delivery are described in U.S. Patent Publication Nos. 2005/0220843 and 2005/0244459.
In addition to the desirable drug-release profiles, many of the coatings that are formed using hydrophobic polymeric systems are durable and compliant. These properties are desirable as the surface of the device typically encounters frictional forces. A durable and compliant coating will generally not be damaged if the coated device is subject to bending or manipulation, which often occurs with stents. These properties prevent the coating from delaminating or cracking during use.
In addition, coatings formed from hydrophobic polymeric systems can be relatively thin, which is also a desirable property when the coating is formed on medical devices having complex geometries. Compositions and methods that allow the formation of thin coatings of polymeric material on the device surface can prevent formation of webs of polymeric material between features of the device.
While these references appear to have demonstrated suitable coating systems for hydrophobic drug release, systems for hydrophilic drug release are not as well developed. Coatings designed to release a hydrophilic bioactive agent have been problematic because release is typically inadequately controlled. These coatings may also the lack desirable physical properties, such as durability.
In many cases, the majority of the hydrophilic bioactive agent is released from the coating in a short burst, resulting in depletion of the bioactive agent from the coating. This burst is particularly undesirable when a therapeutic effect is required over an extended period of time. This short term burst is thought to be caused by the hydrophilicity of the bioactive agent driving water into the polymeric coating, causing an increase in the osmotic pressure in the coating. As a result, the permeability of the coating for the hydrophilic drug is significantly increased, resulting in the elution of the drug at a therapeutically ineffective rate. This effect can happen in coatings having both smaller and larger hydrophilic molecules
Controlling the permeability of water into the polymer coating by reducing the hydrophilicity of the coating, for example, by using a hydrophobic polymer, can provide one way of minimizing water absorption and the inadequate release of the hydrophilic bioactive agent. As indicated, hydrophobic polymers are preferred for the benefits of durability and conformity.
However, the hydrophobic polymer may be incompatible with solvent systems that are required to dissolve the hydrophilic drug. The hydrophilic drug may rapidly phase separate in an uncontrolled manner resulting in drug aggregation in the coating. This system can therefore produce coatings with unpredictable and variable release rate profiles. This situation is undesirable, as coatings displaying reproducible release rates cannot be formed. Furthermore, particles of hydrophilic drug also weaken a hydrophobic coating and cause local areas of high swelling.
Preparing coatings having hydrophilic properties is also challenging from the standpoint of designing hydrophilic bioactive agent-releasing coatings. Coatings that are highly hydrophilic can rapidly absorb water and cause plasticization of the polymer, resulting in a soft gel-like coating. This characteristic is also undesirable as the polymer can tear upon expansion, resulting in partial or full destruction of the coating. Furthermore, excessive water swelling not only weakens the polymer, but may increase the diffusivity of the drug, resulting in loss of release control.